Hydroxylamine derivatives and their use as metalloproteinase inhibiting agents

ABSTRACT

The invention provides hydroxylamine derivatives of formula (I) wherein A, R 1 , R 2  and R 3  have the significance given in the description, which are matrix metalloproteinase inhibitors and which also prevent TNF release. They are therefore useful for the control or prevention of degenerative joints diseases such as rheumatoid arthritis and osteoarthritis or for the treatment of invasive tumours, atherosclerosis or multiple sclerosis. They can be manufactured according to generally known methods. ##STR1##

The present invention is concerned with hydroxylamine derivatives.

The hydroxylamine derivatives provided by the present invention arecompounds of the general formula ##STR2## wherein A represents a groupof the formula ##STR3## R¹ represents cyclopropyl, cyclobutyl orcyclopentyl; R² represents hydrogen, hydroxy, lower alkyl or a group ofthe formula --(CH₂)_(n) -aryl or --(CH₂)_(n) -Het in which n stands for1-4 and Het represents a 5- or 6-membered N-heterocyclic ring which (a)is attached via the N atom, (b) optionally contains N, O and/or S asadditional hetero atom(s) in a position or positions other than adjacentto the linking N atom, (c) is substituted by oxo on one or both C atomsadjacent to the linking N atom and (d) is optionally benz-fused oroptionally substituted on one or more other carbon atoms by lower alkylor oxo and/or on any additional N atom(s) by lower alkyl or aryl; and

R³ represents hydrogen or lower alkyl optionally substituted by aryl,amino, protected amino, di(lower alkyl)amino, guanidino, carboxyl,protected carboxyl, carbamoyl, pyrrolidino, piperidino or morpholino;

and pharmaceutically acceptable salts thereof.

The compounds of formula I possess valuable pharmacological properties.In particular, they are matrix metalloproteinase inhibitors and can alsoprevent TNF release. They can be used in the control or prevention ofdegenerative joint diseases such as rheumatoid arthritis andosteoarthritis or in the treatment of invasive tumours, atherosclerosisor multiple sclerosis.

Objects of the present invention are the compounds of formula I andtheir pharmaceutically acceptable salts per se and for use astherapeutically active substances; a process for the manufacture of saidcompounds and salts; intermediates useful in said process; medicamentscontaining said compounds and salts and the manufacture of thesemedicaments; the use of said compounds and salts in the control orprevention of illnesses or in the improvement of health, especially inthe control or prevention of degenerative joint diseases or in thetreatment of invasive tumours or atherosclerosis, or for the manufactureof a medicament for the control or prevention of degenerative jointdiseases or for the treatment of invasive tumours, atherosclerosis ormultiple sclerosis.

As used in this Specification, the term "lower" means that the groupqualified thereby is a straight-chain or branched-chain group containinga maximum of 7, preferably a maximum of 4, carbon atoms. Examples oflower alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec.butyl, tert.butyl, n-pentyl and n-hexyl. The term "aryl"means an optionally substituted phenyl or naphthyl group, with thesubstituent(s) being selected from halogen (i.e. fluorine, chlorine,bromine or iodine), trifluoromethyl, lower alkyl, lower alkoxy (e.g.methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert.butoxy etc.), phenyland the like.

The terms "protected amino" and "protected carboxy" mean amino andcarboxy groups, respectively, which are protected in a manner known perse, e.g. as in peptide chemistry. Thus, an amino group can be protectedby a benzyloxycarbonyl, tert. butoxycarbonyl, trifluoroacetyl or likegroup. A carboxy group can be protected in the form of a readilycleavable ester such as the methyl, ethyl, benzyl or like ester.

The compounds of formula I form pharmaceutically acceptable salts withbases such as alkali metal hydroxides (e.g. sodium hydroxide andpotassium hydroxide), alkaline earth metal hydroxides (e.g. calciumhydroxide and magnesium hydroxide), ammonium hydroxide and the like. Thecompounds of formula I which are basic form pharmaceutically acceptablesalts with acids. As such salts there come into consideration not onlysalts with inorganic acids such as hydrohalic acids (e.g. hydrochloricacid and hydrobromic acid), sulphuric acid, nitric acid, phosphoric acidetc, but also salts with organic acids such as acetic acid, tartaricacid, succinic acid, fumaric acid, maleic acid, malic acid, salicylicacid, citric acid, methanesulphonic acid, p-toluenesulphonic acid etc.

The compounds of formula I contain at least two asymmetric carbon atomsand can accordingly exist as optically active enantiomers, asdiastereoisomers or as racemates. The present invention is intended toembrace all of these forms.

In the compounds of formula I above, A preferably represents a group ofthe formula (a).

R² preferably represents hydrogen, a group of the formula --(CH₂)_(n)-aryl, especially where the aryl group is unsubstituted phenyl, or agroup of the formula --(CH₂)_(n) -Het, especially where Het optionallycontains as additional hetero atom(s) one or two N atoms, one N atom andone O atom or one O atom. Examples of such groups denoted by Het arethose of the formulae: ##STR4## in which R⁴ and R⁵ each representhydrogen or together represent an additional bond or the remainder of afused benzene ring;

R⁶ represents hydrogen, lower alkyl or aryl;

X represents --CO--, --CH₂ --, --CH(lower alkyl)--, --C(lower alkyl)₂--, --NH--, --N(lower alkyl)-- or --O--; or, when R⁶ represents loweralkyl and X represents --N(lower alkyl), the lower alkyl groups can bejoined to form a 5-, 6- or 7-membered ring; and

Y represents --O--, --NH-- or --N(1-6C alkyl)--.

In an especially preferred embodiment Het represents a group of formula(b), particularly phthalimido, or (c), particularly3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl.

R³ preferably represents unsubstituted lower alkyl, especially methyl.

Particularly preferred compounds of formula I above are:

N2-[3-Cyclobutyl-2(R orS)-[(hydroxycarbamoyl)methyl]propionyl]-N1,3-dimethyl-L-valinamide,

N2-[3-cyclopropyl-2(R orS)-[(hydroxycarbamoyl)methyl]propionyl]-N1,3-dimethyl-L-valinamide,

N2-[3-cyclopentyl-2(R orS)-[(hydroxycarbamoyl)methyl]propionyl]-N1,3-dimethyl-L-valinamide,

N2-[3-cyclopropyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-N1,3-dimethyl-L-valinamideand

N2-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-N1,3-dimethyl-L-valinamide.

Other particularly preferred compounds of formula I are:

N2-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-4-phenyl-butyl]propionyl]-N1,3-dimethyl-L-valinamideand

N2-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-4-phenyl-butyl]propionyl]-N1,3-dimethyl-L-valinamide.

According to the process provided by the present invention, thecompounds of formula I hereinbefore and their pharmaceuticallyacceptable salts are manufactured by

a) reacting an acid of the general formula ##STR5## wherein R¹, R² andR³ have the significance given earlier, with a compound of the generalformula

    H.sub.2 NOZ                                                (III)

wherein Z represents hydrogen, tri(lower alkyl)silyl or diphenyl(loweralkyl)silyl,

and, where required, cleaving off any diphenyl(lower alkyl)silyl grouppresent in the reaction product, or

b) catalytically hydrogenating a compound of the general formula##STR6## wherein R¹, R² and R³ have the significance given earlier andBz represents benzyl, or

c) reacting a hydroxylamine of the general formula ##STR7## wherein R¹,R² and R³ have the significance given earlier, with formic acid andacetic anhydride and, where required, treating the reaction product withan inorganic base, and,

if desired, converting a compound of formula I obtained into apharmaceutically acceptable salt.

The reaction of an acid of formula II with a compound of formula III inaccordance with embodiment (a) of the process can be carried out in aknown manner, for example in an inert organic solvent such asdichloromethane, dimethylformamide or the like usinghydroxybenzo-triazole in the presence of a condensation agent such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride at about 0°C. to about room temperature. Preferred compounds of formula III arethose in which Z represents tert.butyldimethylsilyl ortert.butyldiphenylsilyl. When a compound of formula III in which Zrepresents tri(lower alkyl)silyl is used, this group is cleaved offduring the reaction and working-up, and a compound of formula I isobtained directly. On the other hand, when a compound of formula III inwhich Z represents diphenyl(lower alkyl)silyl is used, this groupremains in the reaction product and must subsequently be cleaved off ina known manner, for example by means of fluoride ions.

The catalytic hydrogenation of a compound of formula IV in accordancewith embodiment (b) of the process can be carried out in a manner knownper se; for example in an inert organic solvent using hydrogen in thepresence of a noble metal catalyst. Suitable inert organic solvents are,for example, lower alkanols such as methanol, ethanol, etc. With respectto the catalyst, this can be, for example, a platinum, palladium orrhodium catalyst which can be supported on a suitable carrier material.Palladium-on-charcoal is the preferred catalyst. The temperature andpressure are not critical, although for convenience the catalytichydrogenation is preferably carried out at room temperature and underatmospheric pressure.

Embodiment c) of the process is conveniently carried out by adding ahydroxylamine of formula V to a mixture of formic acid and aceticanhydride, especially a 1:1 mixture by volume, at about roomtemperature. The reaction product contains, or comprises mainly, the0-acetate corresponding to formula I [A=group (b)] and is converted intothe desired compound of formula I by treatment with an inorganic base,especially an alkali metal bicarbonate such as sodium or potassiumcarbonate. This treatment is suitably carried out in a lower alkanol,preferably methanol.

Compounds of formula I can be converted into pharmaceutically acceptablesalts by treatment with bases and basic compounds of formula I can beconverted into pharmaceutically acceptable salts by treatment withacids. Such treatments can be carried out in a conventional manner.

The acids of formula II which are used as starting materials inembodiment (a) of the process are novel and form a further object of thepresent invention. The acids of formula II in which R² representshydroxy, lower alkyl or a group of the formula --(CH₂)_(n) -aryl or--(CH₂)_(n) -Het can be prepared, for example, as illustrated inReaction Scheme I hereinafter in which R¹, R³ and Bz have thesignificance given earlier, R²¹ represents hydroxy, lower alkyl or agroup of the formula --(CH₂)_(n) -aryl or --(CH₂)_(n) -Het and tBurepresents tert.butyl: ##STR8##

Having regard to Reaction Scheme I, the individual steps thereof can becarried out according to methods known per se. Thus, in the first step,an amino acid of formula VI, which can be obtained according to theprocedure described by Chenault H. K, Dahmer J. and Whitesides G. M.,J.Am. Chem. Soc. 1989, 111, 6354-6364, is converted by treatment withsodium nitrite in the presence of concentrated sulphuric acid into ahydroxy acid of formula VII which is subsequently reacted with benzylbromide in the presence of an organic base, e.g. a trialkylamine such astriethylamine, into a corresponding benzyl ester of formula VIII. Thelatter is then activated, e.g. by reaction withtrifluoromethanesulphonic anhydride, and treated with benzyl tert-butylmalonate in the presence of a strong base, e.g. an alkali metal hydridesuch as sodium hydride, to give a compound of formula IX. The group R²¹is then introduced into the compound of formula IX either by treatmentwith a strong base, e.g. an alkali metal hydride such as sodium hydride,and reaction with a compound of the formula R²² Br, wherein R²²represents lower alkyl or a group of the formula --(CH₂)_(n) -aryl or--(CH₂)_(n) -Het, or by reaction with oxodiperoxymolybdenum(pyridine)hexamethyl-phosphoramide in order to introduce a hydroxy group. Theresulting dibenzyl tert-butyl butanetricarboxylate of formula X is thendebenzylated by catalytic hydrogenation, e.g. in the presence of apalladium catalyst such as palladium-on-charcoal, to give a tert-butyldihydrogen butanetricarboxylate of formula XI. Decarboxylation of thiscompound, e.g. by heating in toluene with triethylamine, which may becarried out in situ, yields a tert-butyl hydrogen succinate of formulaXII which is condensed with an amine of formula XIII, e.g. using1-hydroxybentriazole in the presence of a condensation agent such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, to give acompound of formula XIV which is deprotected (e.g. by treatment withtrifluoroacetic acid) to give an acid of formula IIa.

The acids of formula II in which R² represents hydrogen can be prepared,for example, as illustrated in Reaction Scheme II hereinafter in whichR¹, R³, Bz and tBu have the significance given earlier: ##STR9##

Having regard to Reaction Scheme II, the individual steps of which canbe carried out according to methods known per se, the first stepcomprises reacting dibenzyl malonate of formula XV, which is a knowncompound, with an appropriate cycloalkyl-methyl bromide of formula XVI,which is also a known compound, to give a compound of formula XVII. Thelatter is then reacted with tert.butyl bromoacetate of formula XVIII andthe resulting compound of formula XIX is converted into an acid offormula IIb by debenzylation and decarboxylation, condensation with acompound of formula XIII and finally deprotection in a manner analogousto that described in connection with Reaction Scheme I.

The compounds of formula IV which are used as starting materials inembodiment (b) of the process are novel and form a further object of thepresent invention.

The compounds of formula IV can be prepared, for example, by reacting anacid of formula II with O-benzylhydroxylamine. This reaction can becarried out in a known manner, for example in an inert organic solventsuch as dichloromethane or dimethylformamide using hydroxybenzotriazolein the presence of a condensation agent such as1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride.

The compounds of formula V which are used as starting materials inembodiment c) of the process are novel and form a further object of thepresent invention.

The compounds of formula V can be prepared, for example, as illustratedin Reaction Scheme III hereinafter in which R¹, R² and R³ have thesignificance given earlier: ##STR10##

In the first step of Reaction Scheme III an acid of formula II in aninert solvent, e.g. dichloromethane or dimethylformamide, can be treatedwith the ammonium salt of 1-hydroxybenzotriazole in the presence of atertiary amine such as N-ethylmorpholine and a condensation agent suchas 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, suitablyat about 0° C. to room temperature, to give an amide of formula XXII.This amide can then be rearranged in the second step in a Hofmannreaction, for example by treatment withbis[(trifluoroacetoxy)iodo]benzene in aceto-nitrile/water, suitably atabout room temperature and under an inert gas such as nitrogen. Theresulting amine of formula XXIII can subsequently be converted into thedesired hydroxylamine starting material of formula V by treatment withan oxidizing agent such as 3-chloroperbenzoic acid,1,1-dimethyldioxirane or 1-trifluoromethyl-1-methyldioxirane at a lowtemperature, e.g. about -78° C.

As mentioned earlier, the compounds of formula I and theirpharmaceutically acceptable salts are matrix metalloproteinaseinhibitors.

The inhibitory activity against one such enzyme, collagenase, can bedemonstrated using the test procedure described hereinafter:

This test demonstrates the in vitro collagenase inhibiting activity andis carried out using collagenase obtained from a culture of humansynovial fibroblasts according to the method of Dayer J-M et al., Proc.Natl. Acad. Sci.

USA (1976), 73 945, following activation of the pro-collagenase in theconditioned medium by treatment with trypsin. Collagenase activity wasmeasured using ¹⁴ C-acetylated collagen type I from rat tail tendons asthe substrate and employing the microtitre plate assay method ofJohnson-Wint, B, Anal. Biochem. (1980), 104, 175. The IC₅₀ is thatconcentration of a test compound in the enzyme digestion which reducessubstrate cleavage and solubilization to 50% of that achieved by theenzyme alone.

The results obtained in the foregoing test with representativehydroxamic acid derivatives provided by this invention are compiled inthe following Table:

                  TABLE                                                           ______________________________________                                        Compound of Example                                                                             Test A                                                        No IC.sub.50  (nM)                                                          ______________________________________                                        1                 2.0                                                           2 7.0                                                                         3 5.0                                                                         4 1.0                                                                         5 1.0                                                                       ______________________________________                                    

The compunds of formula I and their pharmaceutically acceptable saltscan be used as medicaments, for example in the form of pharmaceuticalpreparations. The pharmaceutical preparations can be administeredorally, e.g. in the form of tablets, coated tablets, dragees, hard andsoft gelatine capsules, solutions, emulsions or suspensions. However,they ca also be administered rectally, e.g. in the form ofsuppositories, or parenterally, e.g. in the form of injection solutions.

For the manufacture of pharmaceutical preparations the compounds offormula and their pharmaceutically acceptable salts can be formulatedwith therapeutically inert, inorganic or organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts can beused, for example, as such carriers for tablets, coated tablets, drageesand hard gelatine capsules. Suitable carriers for soft gelatine capsulesare, for example, vegetable oils, waxes, fats, semi-solid and liquidpolyols and the like. Depending on the nature of the active ingredientno carriers are, however, generally required in the case of softgelatine capsules. Suitable carriers for the manufacture of solutionsand syrups are, for example, water, polyols, saccharose, invert sugar,glucose and the like. Suitable carriers for the manufacture of injectionsolutions are, for example, water, alcohols, polyols, glycerine,vegetable oils and the like. Natural and hardened oils, waxes, fats,semi-liquid polyols and the like are suitable carriers for themanufacture of suppositories.

The pharmaceutical preparations can also contain preservatives,stabilizers, wetting agents, emulsifiers, sweeteners, colorants,flavorants, salts for adjustment of the osmotic pressure buffers coatingagents or antioxidants.

Medicaments containing a compound of formula I or a pharmaceuticallyacceptable salt thereof and a therapeutically acceptable carrier as wellas a process for the manufacture of such medicaments are also objects ofthe present invention. This process comprises mixing a compound offormula I or a pharmaceutically acceptable salt thereof with atherapeutically inert carrier material and bringing the mixture into agalenical administration form.

As mentioned earlier, the compounds of formula I and theirpharmaceutically acceptable salts can be used in the control orprevention of illnesses, especially in the control or prevention ofdegenerative joint diseases or in the treatment of invasive tumours,atherosclerosis or multiple sclerosis. The dosage can vary within widelimits and will, of course, be adjusted to the individual requirementsin each particular case. In general, in the case of administration toadults, a daily dosage of from about 5 mg to about 30 mg, preferablyfrom about 10 mg to about 15 mg, should be appropriate, although theupper limit may be exceeded when this is found to be expedient. Thedaily dosage can be administered as a single dosage or in divideddosages.

The following Examples illustrate the present invention.

EXAMPLE 1

A solution of 0.36 g of N2-[2(R orS)-[(benzyloxycarbamoyl)methyl]-3-cyclobutylpropionyl]-N1,3-dimethyl-L-valinamide(diastereoisomer 1) in 10 ml of methanol was hydrogenated in thepresence 0.05 g of 5% palladium on charcoal for 11/2 hours. The catalystwas removed by filtration and the solution was evaporated. The resultingsolid was washed with 2 ml of cold methanol to give 0.19 g ofN2-[3-cyclobutyl-2(R orS)-[(hydroxycarbamoyl)-methyl]propionyl]-N1,3-dimethyl-L-valinamide(diastereoisomer 1) as a white solid.

nmr (d₄ MeOH): 4.18(s,1H); 2.8-2.72 (m,1H); 2.7 (s,3H); 2.34-2.1 (m,3H);2.09-2.02 (m,1H); 1.98-1.9 (m,1H); 1.85-1.54 (m,5H); 1.5-1.43 (m,1H);0.96 (s,9H). MS 328 (M+H)⁺.

The starting material was prepared as follows:

(i) 1.1 g of 80% sodium hydride dispersion in mineral oil were addedportionwise to a stirred solution of 10.02 g of dibenzyl malonate in 100ml of 1,2-dimethoxyethane under nitrogen. After the effervescence hadsubsided a solution of 5 g of cyclobutylmethyl bromide in 10 ml of1,2-dimethoxyethane was added. The solution was heated at 60° C.overnight and then left to cool. The solvent was removed by evaporationto leave an oil which was redissolved in 100 ml of ethyl acetate. Thesolution was washed with water and then dried over anhydrous magnesiumsulphate. The solvent was removed by evaporation to leave a pale yellowoil. Flash chromatography on silica gel using 10% ethyl acetate inhexane for the elution gave 1.83 g of dibenzyl cyclobutylmethylmalonate.

MS 353 (M+H)⁺.

Rf [hexane/ethyl acetate (9:1)]=0.57.

(ii) 0.15 g of sodium hydride dispersion in mineral oil was added to astirred solution of 1.65 g of dibenzyl cyclobutylmethyl malonate in 10ml of 1,2-dimethoxyethane under nitrogen. The mixture was stirred atroom temperature for 1.25 hours and then a solution of 0.96 g oftert-butyl bromoacetate in 1 ml of 1,2-dimethoxyethane was added. Thesolution was stirred at room temperature overnight and then the solventwas removed by evaporation. The residual oil was redissolved in ethylacetate, washed with water, saturated sodium chloride solution and thendried over anhydrous magnesium sulphate. The solvent was removed to give1.12 g of 2,2-dibenzyl 3-tert-butyl 1-cyclobutyl-2-propanetricarboxylateas an oil which was used without further purification.

MS 467 (M+H)⁺.

Rf [hexane/ethyl acetate (4:1)]=0.64.

(iii) A solution of 2.1 g of 2,2-dibenzyl 3-tert-butyl1-cyclobutyl-2-propanetricarboxylate in 20 ml of propan-2-ol washydrogenated in the presence of 200 mg of 5% palladium on charcoal for 2hours. The catalyst was removed by filtration and the solvent wasevaporated to leave a colourless oil which was redissolved in 25 ml oftoluene. 0.62 ml of triethylamine was added and the solution was heatedat reflux for 1.25 hours. The mixture was cooled, diluted with 75 ml oftoluene and washed with 2M hydrochloric acid. The organic layer wasdried over anhydrous magnesium sulphate and evaporated to leave 1.14 gof 4-tert-butyl hydrogen 2(RS)-(cyclobutylmethyl)succinate as acolourless oil which was used without further purification.

MS 243 (M+H)⁺.

Rf [dichloromethane/methanol (9:1)]=0.63.

(iv) 0.69 g of 1-hydroxybenzotriazole, 0.87 g of1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride and 1.05 mlof N-ethylmorpholine were added to a stirred solution of 1 g of4-tert-butyl hydrogen 2(RS)-(cyclobutylmethyl)succinate in 25 ml ofdichloromethane at 0° C. The mixture was stirred at 0° C. for 1 hour andthen 0.71 g of (S)-tertbutylglycine methylamide was added. The mixturewas stirred at 0° C. for 1 hour and then at room temperature overnight.The mixture was diluted with 100 ml of dichloromethane and washed insuccession with 5% sodium hydrogen carbonate solution, 2M hydrochloricacid solution and saturated sodium chloride solution. The organic layerwas dried over anhydrous magnesium sulphate. The solvent was removed byevaporation to give 1.37 g ofN2-[2(RS)[tert-butoxycarbonylmethyl]-3-cyclobutylpropionyl]-N1,3-dimethyl-L-valeramideas a 1:1 mixture of diastereoisomers in the form of a white foam.

nmr (CDCl₃): 6.68-6.6 (m,0.5H); 6.5-6.42 (m,1H); 6.25 (d,J=9,0.5H); 4.31(d,J=8,0.5H); 4.26 (d,J=8,0.5H); 2.85 (d,J=4,1.5H); 2.78 (d,J=4,1.5H);2.7-1.5 (m,12H); 1.45 (s,4.5H); 1.43 (s,4.5H); 1.08 (s,4.5H); 1.00(s,4.5H).

MS 369 (M+H)⁺.

(v) A solution of 1.37 g ofN2[2(RS)[tert-butoxycarbonylmethyl]-3-cyclobutylpropionyl]-N1,3-dimethyl-L-valinamideas a 1:1 mixture of diastereoisomers in 20 ml of trifluoroacetic acidwas stirred at room temperature for 2.5 hours. The solvent was removedby evaporation to leave an oil which was partitioned between diethylether and 5% sodium hydrogen carbonate solution. The aqueous phase wasacidified with hydrochloric acid and extracted with dichloromethane. Theorganic layer was dried over anhydrous magnesium sulphate and thenevaporated to give 1.2 g ofN2-[2(RS)[carboxymethyl]-3-cyclobutylpropionyl]-N1,3-dimethyl-L-valinamideas a 1:1 mixture of diastereoisomers in the form of a white foam.

MS 313 (M+H)⁺.

(vi) 0.59 g of 1-hydroxybenzotriazole, 0.74 g of1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride and 0.89 mlof N-ethylmorpholine were added to a stirred solution of 1.1 g ofN2-[2(RS)[carboxymethyl]-3-cyclobutylpropionyl]-N1,3-dimethyl-L-valinamidein 20 ml of dichloro-methane at 0° C. The mixture was stirred at 0° C.for 1 hour and then a solution of 0.54 g of O-benzylhydroxylamine in 1ml of dichloromethane was added. The mixture was stirred at OOC for 1hour and then at room temperature overnight. The solution was dilutedwith 50 ml of dichloro-methane, washed in succession with 5% sodiumhydrogen carbonate solution and 2M hydrochloric acid and then dried overanhydrous magnesium sulphate. The solvent was evaporated to leave 1.08 gof a white foam. Flash chromatography on silica gel using 2% methanol inethyl acetate for the elution gave 0.39 g of N2-[2(R orS)-[(benzyloxycarbamoyl)-methyl]-3-cyclobutylpropionyl]-N1,3-dimethyl-L-valinamide(diastereoisomer 1) in the form of a white foam and 0.44 g ofN2-[3-cyclobutyl-2(R orS)-[(benzyloxycarbamoyl)methyl]propionyl]-N1,3-dimethyl-L-valanamide(diastereoisomer 2) in the form of a white foam.

Diastereoisomer 1.

nmr (CDCl₃): 9.5 (bs,1H); 7.32-7.23 (m,5H); 6.9 (d,J=9,1H); 6.7 (bs,1H);4.81 (s,2H); 2.89-2.81 (m,1H); 2.74-2.65 (m,4H); 2.38-2.30 (m,1H);2.18-2.10 (m,2H); 2.01-1.8 (m,2H); 1.76-1.38 (m,5H); 0.9 (s,9H).

MS 418 (M+H)⁺.

EXAMPLE 2

In a manner analogous to that described in the first paragraph ofExample 1, from 2.3 g of N2-[2(R orS)-[(benzyloxycarbamoyl)methyl]-3-cyclopropylpropionyl]-N1,3-dimethyl-L-valinamide(diastereoisomer 1), prepared in a manner analogous to that described inExample l(i)-(vi), there were obtained 1.69 g of N2-[3-cyclopropyl-2(Ror S)-[(hydroxycarbamoyl)-methyl]propionyl]-N1,3-dimethyl-L-valinamide(diastereoisomer 1) as an off-white solid.

nmr (d₄ MeOH): 4.24 (s,1H); 3.0-2.92 (m,1H); 2.71 (s,3H); 2.36(dd,J=13,7,1H); 2.22 (dd,J=13,6,1H); 1.4-1.32 (m,2H); 0.98 (s,9H);0.78-0.6 (m,1H); 0.45-0.38 (m,1H); 0.36-0.31 (m,1H); 0.05- -0.03 (m,2H)MS 314 (M+H)⁺.

EXAMPLE 3

In a manner analogous to that described in the first paragraph ofExample 1, from 1 g of N2-[2(R orS)-[(benzyloxycarbamoyl))methyl]-3-cyclopentylpropionyl]-N1,3-dimethyl-L-valinamide(diastereoisomer 1), prepared in a manner analogous to Example1(i)-(vi), there was obtained 0.79 g of N2-[3-cyclopentyl-2(R orS)-[(hydroxycarbamoyl)methyl]propionyl]-N1-3-dimethyl-L-valinamide(diastereoisomer 1) as a white solid.

nmr (d₄ MeOH): 4.2 (s,1H); 2.92-2.85 (m,1H); 2.68 (s,3H); 2.3(dd,J=14,9,1H); 2.17 (dd,J=14,6,1H); 1.88-1.78 (m,1H); 1.74-1.28(m,10H); 1.15-1.02 (m,1H); 0.97 (s,9H).

MS 342 (M+H)⁺.

EXAMPLE 4

A solution of 0.47 g of N2-[2(R)-[1(R orS)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopropylpropionyl]-N1,3-dimethyl-L-valinamide(as a 6:1 mixture of diastereoisomers) in 10 ml of ethanol washydrogenated in the presence of 0.17 g of 5% palladium on charcoal for 5hours. The catalyst was removed by filtration and the solvent wasevaporated to leave a solid. Flash chromatography on silica gel using 5%methanol in dichloromethane for the elution gave 0.23 g ofN2-[3-cyclopropyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-N1,3-dimethyl-L-valinamide(diastereoisomer 1) as a white solid.

nmr (d₄ MeOH): 4.37 (s,1H); 3.9-3.85 (m,1H); 3.43 (dd, J=14,4,1H); 2.9(s,3H); 2.88-2.83 (m,2H); 2.75 (s,3H); 1.45-1.32 (m,8H); 1.08 (s,9H);0.66-0.57 (s,1H); 0.46-0.40 (m,1H); 0.38-0.32 (m,1H); 0.05- -0.03(m,2H);

MS 468 (M+H)⁺.

The starting material was prepared as follows:

(i) A solution of 4.9 g of 2(R)-amino-3-cyclopropylpropionic acid(prepared in a manner analogous to that described by Chenault H. K.,Dahmer J. and Whitesides G. M. in J. Am. Chem. Soc. 1989, 111,6354-6364) in 50 ml of water containing 4.05 ml of concentratedsulphuric acid was warmed to 45°. A solution of 10.5 g of sodium nitritein 20 ml of water was added dropwise over 30 minutes. The solution wasstirred at 45° for 4 hours and then cooled to room temperature. Thesolution was extracted with three 50 ml portions of ethyl acetate. Thecombined extracts were washed with water and dried over anhydrousmagnesium sulphate. The solvent was evaporated to leave 3.95 g of ayellow oil containing 3-cyclopropyl-2(R)-hydroxypropionic acid which wasused in the next step without further purification.

Rf [dichloromethane/methanol (9:1)]=0.65.

(ii) A solution of 3.95 g of 3-cyclopropyl-2(R)-hydroxypropionic acid in50 ml of ethyl acetate was treated with 5.32 ml of triethylamine and 3.8ml of benzyl bromide. The mixture was stirred and heated under refluxfor 3 hours, then allowed to cool to room temperature overnight. Thesuspension was washed with 2M hydrochloric acid, water and saturatedsodium chloride solution. After drying over anhydrous magnesium sulphatethe solvent was evaporated. The residue was purified by flashchromatography on silica gel using hexane/ethyl acetate (2:1) for theelution to give 3.36 g of benzyl 3-cyclopropyl-2(R)-hydroxypropionate inthe form of a yellow oil.

nmr (CDCl₃): 7.39-7.28 (m; 5H); 5.19 (d, 1H, J=14); 5.15 (d, 1H, J=14);4.31-4.24 (m, 1H); 2.81 (br. d, IH); 1.69-1.54 (m, 2H); 0.87-0.74 (m,1H); 0.45-0.34 (m, 2H); 0.08- -0.07 (m, 2H).

(iii) A solution of 3.36 g of benzyl3-cyclopropyl-2(R)-hydroxypropionate and 1.49 ml of pyridine in 10 ml ofdichloromethane was added dropwise to a solution of 3.07 ml oftrifluoromethanesulphonic anhydride in 15 ml of dichloromethane at 0°over 30 minutes with stirring. The mixture was stirred at 0° for 2 hoursand then washed with water and saturated sodium chloride solution. Afterdrying over anhydrous magnesium sulphate the solvent was evaporated togive 5.37 g of benzyl3-cyclopropyl-2(R)-trifluoro-methylsulphonyloxypropionate in the form ofan orange oil which was used in the next step without furtherpurification.

Rf [hexane/ethyl acetate (4:1)]=0.5.

(iv) A solution of 3.8 g of benzyl tert-butyl malonate in 50 ml of1,2-dimethoxyethane was treated with 0.504 g of an 80% dispersion ofsodium hydride in mineral oil. The mixture was stirred at roomtemperature for 30 minutes and then cooled to 0°. A solution of 5.37 gof benzyl 3-cyclopropyl-2(R)-trifluoromethylsulphonyloxypropionate in 20ml of dichloromethane was added dropwise at 0°. The mixture was stirredat 0° for 2 hours and then left to warm to room temperature overnight.The solvent was evaporated and the residue was dissolved in ethylacetate. The solution was washed with water and saturated sodiumchloride solution. After drying over anhydrous magnesium sulphate thesolvent was evaporated to give 6.54 g of 2,3-dibenzyl 3-tert-butyl1-cyclopropyl-2(R),3(R,S),3-propane-tricarboxylate as a 1:1 mixture ofdiastereoisomers in the form of an orange oil.

nmr (CDCl₃): 7.46-7.36 (m, 20H); 5.19-5.07 (m, 8.H); 3.89 (d, 1H, J=10);3.85 (d, 1H, J=10) 3.37-3.26 (m, 2H); 1.68-1.52 (m, 2H); 1.52-1.38 (m,2H); 1.41 (s, 9H); 1.39 (s, 9H); 0.79-0.63 (m, 2H); 0.49-0.38 (m, 4H);0.12- -0.07 (m, 4H).

(v) A solution of 6.4 g of 2,3-dibenzyl 3-tert-butyl1-cyclopropyl-2(R),3(R,S),3-propanetricarboxylate (1:1 mixture ofdiastereoisomers) in 30 ml of 1,2-dimethoxyethane was treated with 0.446g of an 80% dispersion of sodium hydride in mineral oil. The mixture wasstirred at room temperature for 30 minutes. A solution of 3.84 g of1-(bromomethyl)-3,4,4-trimethyl-2,5-imidazolinedione in 20 ml of1,2-dimethoxyethane was added dropwise over 15 minutes. The mixture wasstirred at room temperature for 36 hours, the solvent was evaporated andthe residue was dissolved in ethyl acetate and washed with water andsaturated sodium chloride solution. After drying over anhydrousmagnesium sulphate the solvent was evaporated. The residue was purifiedby flash chromatography on silica gel using hexane/ethyl acetate (7:3)and subsequently hexane/ethyl acetate (6:4) for the elution to give 6.4g of 2,3-dibenzyl 3-tert-butyl1-cyclopropyl-4-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)-2(R),3(R,S),3-butanetricarboxylateas a 1:1 mixture of diastereoisomers in the form of a clear oil.

nmr (CDCl₃): 7.47-7.28 (m, 20H); 5.31-5.03 (m, 8H); 4.32-4.18 (m, 4H);3.19-3.15 (m, 1H); 3.16-3.12 (m, 1H); 2.86 (s, 6H); 2.00-1.90 (m, 1H);1.89-1.79 (m, 1H); 1.64-1.49 (m, 1H); 1.48-1.38 (m, 1H); 1.37 (s, 12H);1.36 (s, 9H); 1.32 (s, 9H); 0.9-0.8 (m, 2H); 0.41-0.3 (m, 4H); 0.15-0.05(m, 2H); 0.04- -0.04 (m, 2H).

(vi) A solution of 3.0 g of 2,3-dibenzyl 3-tert-butyl1-cyclopropyl-4-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)-2(R),3(R,S),3-butanetricarboxylate(1:1 mixture of diastereoisomers in 30 ml of 2-propanol was hydrogenatedin the presence of 0.3 g of 5% palladium on charcoal catalyst for 2hours. The catalyst was removed by filtration and the solution wasevaporated. The residue was re-evaporated from 20 ml toluene and thendissolved in 50 ml of toluene. The solution was treated with 0.693 ml oftriethylamine and the mixture was heated under reflux for 2 hours. Thesolution was cooled to room temperature and washed with 2M hydrochoricacid, water and saturated sodium chloride solution. After drying overanhydrous magnesium suphate the solvent was evaporated to give 1.85 g of4-tert-butyl hydrogen 2(R)-(cyclopropylmethyl)-3(R orS)-[(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)methyl]succinate as anapproximately 6:1 mixture of diastereoisomers in the form of a yellowoil.

MS: 383 (M+H)⁺ ;

Rf [dichloromethane/methanol (9:1)]=0.41.

(vii) 0.433 g of 1-hydroxybenzotriazole, 0.542 g of1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride and 0.598ml of N-ethylmorpholine were added to a stirred solution of 0.9 g of4-tert-butyl hydrogen 2(R)-(cyclopropylmethyl)-3(R orS)-[3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)-methyl]succinate(approximately 6:1 misture of diastereoisomers) in 10 ml ofdichloromethane at 0° C. The mixture was stirred at 0° C. for 30 minutesand then a solution of 0.407 g of (S)-tert-butylglycine methylamide in 1ml of dichloromethane was added. The mixture was stirred at 0° C. for 2hours and then at room temperature overnight. The solution was washedwith 5% sodium hydrogen carbonate solution, 2M hydrochloric acid andsaturated sodium chloride solution. The solution was dried overanhydrous magnesium sulphate and evaporated to leave 1.2 g ofN2-[2(R)-[1(R orS)-(tert-butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopropylpropionyl]-1N,3-dimethyl-L-valinamideas a 6:1 mixture of diastereoisomers in the form of a cream foam.

MS 509 (M+H)⁺.

Rf (5% methanol in dichloromethane)=0.55.

(viii) A solution of 1.2 g of N2-[2(R)-[1(R orS)-tert-butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopropylpropionyl]-N1,3-dimethyl-L-valinamide(6:1 mixture of diastereoisomers) in 4 ml of trifluoroacetic acid wasstirred at room temperature for 2 hours. The solution was evaporated andthe residue was partitioned between diethyl ether and 5% sodium hydrogencarbonate. The aqueous phase was acidified with hydrochloric acid andextracted with dichloromethane. The organic layer was dried overanhydrous magnesium sulphate and evaporated to leave an oil. Triturationof the oil with hexane gave 0.65 g of N2-[2(R)-[1(R orS)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopropyl-propionyl]-N1,3-dimethyl-L-valinamideas a 6:1 mixture of diastereoisomers in the form of a white solid whichwas used without further purification.

MS 453 (M+H)⁺.

Rf (10% methanol in dichloromethane)=0.27.

(ix) 0.26 g of 1-hydroxybenzotriazole, 0.33 g of1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride and 0.36 mlof N-ethylmorpholine were added to a stirred solution of 0.65 g ofN2-[2(R)-[2(R orS)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl[-3-cyclopropylpropionyl]-N1,3-dimethyl-L-valinamide(6:1 mixture of diastereoisomers) in 10 ml of dichloromethane at 0° C.The mixture was stirred at 0° C. for 30 minutes and then a solution of0.21 g of O-benzylhydroxylamine in 2 ml of dichloromethane was added.The mixture was stirred at 0° C. for 2 hours and then at roomtemperature overnight. The solution was diluted with 50 ml ofdichloromethane, washed in succession with 5% sodium hydrogen carbonatesolution and 2M hydrochloric acid solution and then dried over anhydrousmagnesium sulphate. The solution was evaporated and the residue wastriturated with diethyl ether to give 0.47 g of N2-[2(R)-[(R orS)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopropylpropionyl]-N1,3-dimethyl-L-valinamideas a 6:1 mixture of diastereoisomers in the form of a white solid.

nmr (d₄ MeOH): 8.22-8.15 (m,1H); 7.5-7.36 (m,5H); 4.95-4.83 (m,2H); 3.85(dd,J=12,8,1H); 3.53 (dd,J=12,5,1H); 2.96-2.86 (m,4H); 2.8-2.68 (m,4H);1.4-1.36 (m,6H); 1.35-1.25 (m,1H); 1.15-1.03 (m,10H); 0.65-0.58 (m,1H);0.48-0.4 (m,1H); 0.37-0.31 (m,1H); 0.12- -0.03 (m,2H).

MS 558 (M+H)⁺.

EXAMPLE 5

In a manner analogous to that described in the first paragraph ofExample 4, from 0.37 g of N2-[2(R)-[1(R orS)-benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]-N1,3-dimethyl-L-valinamide(diastereoisomer 1), prepared in a manner analogous to Example1(i)-(ix), there was obtained 0.27 g of N2-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-N1,3-dimethyl-L-valinamide,diastereo-isomer 1 in the form of a white solid.

nmr (d4 MeOH): 4.19 (s,1H); 3.53(dd,J=12,10); 3.25 (dd,J=14,5); 2.75(s,3H); 2.72-2.62 (m,4H); 2.58-2.52 (m,1H); 2.1-1.92 (m,2H); 1.85-1.27(m,7H); 1.26 (s,6H); 0.93 (s,9H);

MS 482 (M+H)⁺.

EXAMPLE 6

In a manner analogous to that described in the first paragraph ofExample 1, from 0.326 g of N2-[2(R)-[1(R orS)-(benzyloxycarbamoyl)-4-phenylbutyl]-3-cyclobutylpropionyl]-N,3-dimethyl-L-valinamide(diastereoisomer 1), prepared in a manner analogous to that described inExample 4(v)-(ix) using 2,3-dibenzyl 3-tert-butyl 1-cyclobutyl-2(R),3(R,S)3-propanetricarboxylate and cinnamyl bromide, there was obtained0.246 g of N2-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-4-phenylbutyl]propionyl]-N1,3-dimethyl-L-valinamide(diastereoisomer 1) as a white solid.

nmr (d₄ MeOH): 7.23-7.17 (m,2H); 7.13-7.07 (m,3H); 4.20 (s,1H); 2.70(s,3H); 2.59-2.42 (m,3H); 2.24-1.99 (m,3H); 1.94-1.84 (m,1H); 1.81-1.65(m,2H); 1.64-1.29 (m,8H); 0.94 (s,9H); MS 446 (M+H)⁺.

EXAMPLE 7

In a manner analogous to that described in the first paragraph ofExample 1, from 0.227 g of N2-[2(R)-[1(R orS)-(benzyloxycarbamoyl)4-phenylbutyl]-3-cyclopentylpropionyl]-N,3-dimethyl-L-valinamide(diastereoisomer 1), prepared in a manner analogous to that described inExample 4(v)-(ix) using 2,3-dibenzyl 3-tert-butyl 1-cyclopentyl-2(R),3(R,S)-3-propanetricarboxylate, there was obtained 0.173 g ofN2-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-4-phenylbutyl]propionyl]-N1,3-dimethyl-L-valinamide(diastereoisomer 1) as a white solid.

nmr (d₄ MeOH): 7.23-7.16 (m,2H); 7.14-7.06 (m,3H); 4.21 (s,1H); 2.68(s,3H); 2.63-2.49 (m,3H); 2.23-2.14 (m,1H); 1.88-1.78 (m,1H); 1.66-1.32(m,1H); 1.24-1.16 (m,1H); 1.06-0.93 (m,11H); MS 460 (M+H)⁺.

The following Examples illustrate pharmaceutical preparations containingthe hydroxylamine derivatives provided by the present invention:

EXAMPLE A

Tablets containing the following ingredients may be produced in aconventional manner:

    ______________________________________                                        Ingredient         Per tablet                                                 ______________________________________                                        Hydroxylamine derivative                                                                          10.0 mg                                                     Lactose 125.0 mg                                                              Corn starch  75.0 mg                                                          Talc  4.0 mg                                                                  Magnesium stearate  1.0 mg                                                    Total weight 215.0 mg                                                       ______________________________________                                    

EXAMPLE B

Capsules containing the following ingredients may be produced in aconventional manner:

    ______________________________________                                        Ingredient         Per capsule                                                ______________________________________                                        Hydroxylamine derivative                                                                          10.0 mg                                                     Lactose 165.0 mg                                                              Corn starch  20.0 mg                                                          Talc  5.0 mg                                                                  Capsule fill weight 200.0 mg                                                ______________________________________                                    

We claim:
 1. A compounds of the formula ##STR11## wherein A represents agroup of the formula ##STR12## R¹ represents cyclopropyl, cyclobutyl orcyclopentyl; R² represents hydrogen, or a group of the formula--(CH₂)_(n) -aryl, --(CH₂)_(n) -Het in which n stands for 1-4 and Hetrepresents a 5- or 6-membered N-heterocyclic ring which (a) is attachedvia the N atom, (b) optionally contains N, O and/or S as additionalhetero atom(s) in a position or positions other than adjacent to thelinking N atom, (c) is substituted by oxo on one or both C atomsadjacent to the linking N atom and (d) is optionally benz-fused oroptionally substituted on one or more other carbon atoms by lower alkylor oxo and/or on any additional N atom(s) by lower alkyl or aryl; andR³represents hydrogen or lower alkyl optionally substituted by aryl,amino, protected amino, di(lower alkyl)amino, guanidino, carboxyl,protected carboxyl, carbamoyl, pyrrolidino, piperidino or morpholino;andpharmaceutically acceptable salts thereof.
 2. The compound according toclaim 1, wherein A represents a group of formula (a).
 3. Compoundsaccording to claim 1, wherein the aryl group is unsubstituted phenyl. 4.The compounds according to claim 1, wherein Het represents phthalimidoor 3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl.
 5. The Compoundsaccording to claim 1, wherein R³ represents unsubstituted lower alkyl.6. The compounds according to claim 5, wherein R³ represents methyl. 7.A Compound of the formula ##STR13## wherein R¹ represents cyclopropyl,cyclobutyl or cyclopentyl;R² represents hydrogen hydroxy, lower alkyl ora group of the formula --(CH₂)_(n) -aryl, --(CH₂)_(n) -Het in which nstands for 1-4 and Het represents a 5- or 6-membered N-heterocyclic ringwhich (a) is attached via the N atom, (b) optionally contains N, Oand/or S as additional hetero atom(s) in a position or positions otherthan adjacent to the linking N atom, (c) is substituted by oxo on one orboth C atoms adjacent to the linking N atom and (d) is optionallybenz-fused or optionally substituted on one or more other carbon atomsby lower alkyl or oxo and/or on any additional N atom(s) by lower alkylor aryl; and R³ represents hydrogen or lower alkyl optionallysubstituted by aryl, amino, protected amino, di(lower alkyl)amino,guanidino, carboxyl, protected carboxyl, carbamoyl, pyrrolidino,piperidino or morpholino.
 8. A compound of the formula ##STR14## whereinR¹ represents cyclopropyl, cyclobutyl or cyclopentyl,R² representshydrogen, hydroxy, lower alkyl or a group of the formula --(CH₂)_(n)aryl, --(CH₂)_(n) -Het in which n stands for 1-4 and Het represents a 5-or 6-membered N-heterocyclic ring which (a) is attached via the N atom,(b) optionally contains N, O and/or S as additional hetero atom(s) in aposition or positions other than adjacent to the linking N atom, (c) issubstituted by oxo on one or both C atoms adjacent to the linking N atomand (d) is optionally benz-fused or optionally substituted on one ormore other carbon atoms by lower alkyl or oxo and/or on any additional Natom(s) by lower alkyl or aryl, and R³ represents hydrogen or loweralkyl optionally substituted by aryl, amino, protected amino, di(loweralkyl)amino, guanidino, carboxyl, protected carboxyl, carbamoyl,pyrrolidino, piperidino or morpholino.
 9. A compounds of the formula##STR15## wherein R¹ represents cyclopropyl, cyclobutyl orcyclopentyl,R² represents hydrogen, hydroxy, lower alkyl or a group ofthe formula --(CH₂)_(n) -aryl, --(CH₂)_(n) -Het in which n stands for1-4 and Het represents a 5- or 6-membered N-heterocyclic ring which (a)is attached via the N atom, (b) optionally contains N, O and/or S asadditional hetero atom(s) in a position or positions other than adjacentto the linking N atom, (c) is substituted by oxo on one or both C atomsadjacent to the linking N atom and (d) is optionally benz-fused oroptionally substituted on one or more other carbon atoms by lower alkylor oxo and/or on any additional N atom(s) by lower alkyl or aryl; and R³represents hydrogen or lower alkyl optionally substituted by aryl,amino, protected amino, di(lower alkyl)amino, guanidino, carboxyl,protected carboxyl, carbamoyl, pyrrolidino, piperidino or morpholino.10. The compound of claim 1, wherein the compound isN2-[3-Cyclobutyl-2(R orS)-[(hydroxycarbamoyl)methyl]-propionyl]-N1,3-dimethyl-L-valinamide. 11.The compound of claim 1, wherein the compound is N2-[3-cyclopropyl-2(Ror S)-[(hydroxycarbamoyl)methyl]-propionyl]-N1,3-dimethyl-L-valinamide.12. The compound of claim 1, wherein the compound isN2-[3-Cyclopentyl-2(R orS)-[hydroxycarbamoyl)methyl]-propionyl]-N1,3-dimethyl-L-valinamide. 13.The compound of claim 1, wherein the compound isN2-[3-Cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-4-phenyl-butyl]propionyl]-N,1,3-dimethyl-L-valinamide.
 14. The compound of claim 1, wherein thecompound is N2-[3-Cyclopentyl-2(R)-[1(R or S)hydroxycarbamoyl)-4-phenylbutyl]propionyl]-N1,3-dimethyl-L-valinamide.15. A compound of the formula ##STR16## wherein A is a group of theformula ##STR17## R¹ represents cyclopropyl, cyclobutyl or cyclopentyl;R³ represents hydrogen or lower alkyl optionally substituted by aryl,amino, protected amino, di(lower alkyl)amino, guanidino, carboxyl,protected carboxyl, carbamoyl, pyrrolidino, piperidino or morpholino;R²represents --(CH₂)_(n) -Het in which n stands for 1-4, and Het is agroup of the formula ##STR18## in which R⁴ and R⁵ each representhydrogen or together represent an additional bond or the remainder of afused benzene ring; R⁶ represents hydrogen, lower alkyl or aryl; and Xrepresents --CO--, --CH₂ --, --CH(lower alkyl)-, --C(lower alkyl)₂ --,--NH--, --N(lower alkyl)- or --O--; or where R⁶ represents lower alkyland X represents --N(lower alkyl)-, the lower alkyl groups can be joinedto form a 5-, 6-or 7-membered ring.
 16. The compound of claim 15,wherein A represents a group of formula (a).
 17. The compound of claim15, wherein R³ represents unsubstituted lower alkyl.
 18. The compound ofclaim 17, wherein R³ represents methyl.
 19. The compound of claim 15,wherein the compound is N2-[3-Cyclopropyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4,-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-N1,3-dimethyl-L-valinamide.20. The compound of claim 15, wherein the compound isN2-[3-Cylcobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-N1,3-dimethyl-L-valinamide.21. A compound of the formula ##STR19## wherein A is a group of theformula ##STR20## R¹ represents cyclopropyl, cyclobutyl or cyclopentyl;R³ represents hydrogen or lower alkyl optionally substituted by aryl,amino, protected amino, di(lower alkyl)amino, guanidino, carboxyl,protected carboxyl, carbamoyl, pyrrolidino, piperidino or morpholino;andR² represents --(CH₂)_(n) -Het in which n stands for 1-4, and Het isa group of the formula ##STR21##
 22. The compound of claim 21, wherein Arepresents a group of formula (a).
 23. The compound of claim 21, whereinR³ represents unsubstituted lower alkyl.
 24. The compound of claim 23,wherein R³ represents methyl.
 25. A compound of the formula whereinR¹represents cyclopropyl, cyclobutyl or cyclopentyl; R² represents--(CH₂)_(n) -Het in which n stands for 1-4, and Het is a group of theformula ##STR22## in which R⁴ and R⁵ each represent hydrogen or togetherrepresent an additional bond or the remainder of a fused benzene ring;R⁶ represents hydrogen, lower alkyl or aryl; and X represents --CO--,--CH₂ --, --CH(lower alkyl)-, --C(lower alkyl)2--, --NH--, --N(loweralkyl)- or --O--; or where R⁶ represents lower alkyl and X represents--N(lower alkyl)-, the lower alkyl groups can be joined to form a 5-,6-or 7-membered ring; and R³ represents hydrogen or lower alkyloptionally substituted by aryl, amino, protected amino, di(loweralkyl)amino, guanidino, carboxyl, protected carboxyl, carbamoyl,pyrrolidino, piperidino or morpholino.
 26. A compound of the formula##STR23## wherein R¹ represents cyclopropyl, cyclobutyl orcyclopentyl;R² represents --(CH₂)_(n) -Het in which n stands for 1-4,and Het is a group of the formula ##STR24## R³ represents hydrogen orlower alkyl optionally substituted by aryl, amino, protected amino,di(lower alkyl)amino, guanidino, carboxyl, protected carboxyl,carbamoyl, pyrrolidino, piperidino or morpholino.
 27. A compound of theformula ##STR25## wherein R¹ represents cyclopropyl, cyclobutyl orcyclopentyl;R² represents --(CH₂)_(n) -Het in which n stands for 1-4,and Het is a group of the formula ##STR26## in which R⁴ and R⁵ eachrepresent hydrogen or together represent an additional bond or theremainder of a fused benzene ring; R⁶ represents hydrogen, lower alkylor aryl; and X represents --CO--, --CH₂ --, --CH(lower alkyl)-,--C(lower alkyl)₂ --, --NH--, --N(lower alkyl)- or --O--; or where R⁶represents lower alkyl and X represents -N(lower alkyl)-, the loweralkyl groups can be joined to form a 5-, 6-or 7-membered ring; and R³represents hydrogen or lower alkyl optionally substituted by aryl,amino, protected amino, di(lower alkyl)amino, guanidino, carboxyl,protected carboxyl, carbamoyl. pyrrolidino, piperidino or morpholino.28. A compound of the formula ##STR27## wherein R¹ representscyclopropyl, cyclobutyl or cyclopentyl;R² represents --(CH₂)_(n) -Het inwhich n stands for 1-4, and Het is a group of the formula ##STR28## R³represents hydrogen or lower alkyl optionally substituted by aryl,amino, protected amino, di(lower alkyl)amino, guanidino, carboxyl,protected carboxyl, carbamoyl, pyrrolidino, piperidino or morpholino.29. A compound of the formula ##STR29## wherein R¹ representscyclopropyl, cyclobutyl or cyclopentyl;R² represents --(CH₂)_(n) -Het inwhich n stands for 1-4, and Het is a group of the formula ##STR30## inwhich R⁴ and R⁵ each represent hydrogen or together represent anadditional bond or the remainder of a fused benzene ring; R⁶ representshydrogen, lower alkyl or aryl; and X represents --CO--, --CH₂ --,--CH(lower alkyl)-, --C(lower alkyl)2--, --NH--, --N(lower alkyl)- or--O--; or where R⁶ represents lower alkyl and X represents --N(loweralkyl)-, the lower alkyl groups can be joined to form a 5-, 6-or7-membered ring; and R³ represents hydrogen or lower alkyl optionallysubstituted by aryl, amino, protected amino, di(lower alkyl)amino,guanidino, carboxyl, protected carboxyl, carbamoyl, pyrrolidino,piperidino or morpholino.
 30. A compound of the formula ##STR31##wherein R¹ represents cyclopropyl, cyclobutyl or cyclopentyl;R²represents --(CH₂)_(n) -Het in which n stands for 1-4, and Het is agroup of the formula ##STR32## R³ represents hydrogen or lower alkyloptionally substituted by aryl, amino, protected amino, di(loweralkyl)amino, guanidino, carboxyl, protected carboxyl, carbamoyl,pyrrolidino, piperidino or morpholino.
 31. A process for producing acompound of formula: ##STR33## wherein A is a group of the formula##STR34## R¹ represents cyclopropyl, cyclobutyl or cyclopentyl; R²represents hydrogen, hydroxy, lower alkyl or a group of the formula--(CH₂)_(n) -aryl, --(CH₂)_(n) -Het in which n stands for 1-4 and Hetrepresents a 5- or 6-membered N-heterocyclic ring which (a) is attachedvia the N atom, (b) optionally contains N, O and/or S as additionalhetero atom(s) in a position or positions other than adjacent to thelinking N atom, (c) is substituted by oxo on one or both C atomsadjacent to the linking N atom and (d) is optionally benz-fused oroptionally substituted on one or more other carbon atoms by lower alkylor oxo and/or on any additional N atom(s) by lower alkyl or aryl; andR³represents hydrogen or lower alkyl optionally substituted by aryl,amino, protected amino, di(lower alkyl)amino, guanidino, carboxyl,protected carboxyl, carbamoyl, pyrrolidino, piperidino ormorpholino;comprising reacting an acid of formula ##STR35## with acompound of formula H₂ NOZ, wherein Z is hydrogen, tri(lower alkyl)silylor diphenyl(lower alkyl)silyl, and if Z is diphenyl(lower alkyl)silylsubsequently cleaving off any diphenyl(lower alkyl)silyl group presentin the product of the reaction of the acid with the compound of formulaH₂ NOZ, thereby producing the compound of formula I.
 32. A process forproducing a compound of formula: ##STR36## wherein A is a group of theformula ##STR37## R¹ represents cyclopropyl, cyclobutyl or cyclopentyl;R² represents hydrogen, hydroxy, lower alkyl or a group of the formula--(CH₂)_(n) -aryl, --(CH₂)_(n) -Het in which n stands for 1-4 and Hetrepresents a 5- or 6-membered N-heterocyclic ring which (a) is attachedvia the N atom, (b) optionally contains N, O and/or S as additionalhetero atom(s) in a position or positions other than adjacent to thelinking N atom, (c) is substituted by oxo on one or both C atomsadjacent to the linking N atom and (d) is optionally benz-fused oroptionally substituted on one or more other carbon atoms by lower alkylor oxo and/or on any additional N atom(s) by lower alkyl or aryl; andR³represents hydrogen or lower alkyl optionally substituted by aryl,amino, protected amino, di(lower alkyl)amino, guanidino, carboxyl,protected carboxyl, carbamoyl, pyrrolidino, piperidino ormorpholino;comprising catalytically hydrogenating a compound of formula##STR38## wherein Bz is benzyl, thereby producing the compound offormula I.